Catechol-containing adhesive hydrogel, composition for preparing adhesive hydrogel, and compositions each including said adhesive hydrogel

ABSTRACT

A hydrogel that adheres to the surface of materials is provided by using as constituent elements a water-soluble main chain monomer, crosslinking agent, polymerization initiator, and adhesive monomer having at least a catechol group in a side chain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/575,869, filed Nov. 21, 2017, which is a U.S. national phase of PCTInternational Patent Application No. PCT/JP2016/065634, filed May 26,2016, which claims priority to Japanese Patent Application No.2015-106809, filed May 26, 2015, the contents of each of which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to an adhesive hydrogel containing acatechol group, a composition for an adhesive hydrogel, an adhesiveincluding a hydrogel, a bioadhesive, a medical adhesive, a ship bottomantifouling paint, a water-based lubricant, and a coating material forantifouling.

2. Description of the Related Art

A hydrogel is a three-dimensional network structure formed bycrosslinking a polymer. Hydrogels are hydrous, endowed with flexibility,rich in absorbency, and present volume phase transition and aretherefore utilized in various fields such as medical materials andindustrial products. For example, various applications such as woundhealing materials to adhere tissues, adhesives of implants, and matricesfor drug delivery systems (DDS) are being studied as medical materials.

In recent years, imparting various functions to hydrogels in accordancewith their purpose and applying them for the desired purpose have beenstudied. “Smart gels” in which the gel functions autonomously by sensingan outside stimulus such as heat, electricity, light, or pH are alsobeing actively developed. Although hydrogels that have been impartedvarious functions in this way are being developed, their application islimited because hydrogels are endowed with virtually no adhesiveness tothe surface of other materials such as metals.

The main reasons why hydrogels are not endowed with adhesiveness to thesurface of other materials are that water is contained in thethree-dimensional network of the crosslinked polymer of the hydrogel andthe water content is high and that hydrogels are easily structurallydeformed. Various attempts have therefore been made to impartadhesiveness to hydrogels. Methods of introducing photoinitiating groupssuch as phenylazide groups into a substrate and immobilizing a hydrogel,or affixing after having decomposed part of the gel by an excimer laserhave been disclosed to date (Non-patent Documents 1 and 2).

A method of chemically modifying the polymer main chain and introducingan adhesive group has also been disclosed. Patent Document 1 discloses abioinjectable tissue-adhesive hydrogel having tissue adhesive forcethrough bonding with DOPA (3,4-dihydroxyphenylalanine) or a DOPAderivative. DOPA derivatives are adhesive materials discovered to adhereto the surface of various materials such as rocks, trees, metals, andconcrete structures even in environments where mussels typified bycommon blue mussels are exposed to moist environments and severe tides.The catechol groups included in DOPA secreted from the byssus gland ofmussels can adhere firmly to a variety of materials, even in water.Patent Document 1 prepares a hydrogel endowed with adhesiveness bylinking a compound having a DOPA derivative to the main chain of ahydrogel.

Patent Document 2 discloses a method for producing a polymer gel endowedwith adhesiveness by impregnating a base material porous film with apolymer having a polyacrylate structure or the like in the main chainand a chain-like oligoalkylene oxide structure in a side chain.

PRIOR ART DOCUMENTS Patent Documents

-   [Patent Document 1] Published Japanese Translation of PCT    Application No. 2013-503688-   [Patent Document 2] JP Kokai 2003-100349

Non-Patent Documents

-   [Non-patent Document 1] Y. Nakayama, T. Matsuda, Jinko Zoki, 1993,    Vol. 22(2), pp. 394-397.-   [Non-patent Document 2] Y. Nakayama, T. Matsuda, Jinko Zoki, 1995,    Vol. 24(1), pp. 74-78.-   [Non-patent Document 3] Saito, Y. et al., Macromol. Rapid Commun.,    2013, Vol. 34, pp. 630-634.

SUMMARY OF THE INVENTION

The method disclosed in Non-patent Document 1 requires chemicalmodification of the substrate surface and requires a complex procedure.The method disclosed in Non-patent Document 2 requires a strong lightsource. A hydrogel cannot be immobilized simply on a substrate surfaceeven by using either method.

The method described in Patent Document 1 imparts adhesiveness to ahydrogel by introducing a strongly adhesive catechol group into thepolymer main chain. However, all of the catechol groups introducedcannot be utilized in adhesion because the catechol groups introducedinto the main chain are also used in linkage between polymers. Firmadhesive force was therefore not obtained. Moreover, there is apossibility that the hydrogel will fail to hold its shape in thepresence of free catechol, and doubts remain about practicalapplication. In addition, the purpose of the method of Patent Document 2is not firm adhesion, as analyzed by the peeling adhesive strength inthe examples, and the adhesiveness was inadequate. The purpose of thepresent invention is to provide a hydrogel endowed with firm enoughadhesive force to be able to function even as an adhesive.

All of the catechol groups introduced function effectively as adhesiblegroups by causing the catechol groups, which are adhesive molecules, tobe contained in a side chain rather than the main chain. The adhesiveforce can also be adjusted since the amount of catechol groups includedin the side chain can be adjusted freely. However, there are problemssuch as the selection of the main chain monomer that polymerizes withthe monomer containing a catechol group in a side chain and functions asa hydrogel and the fact that polymerization ceases because of a declinein the polarity of the catechol monomer due to imparting polymerizablegroups; and it was difficult to realize a hydrogel that caused catecholgroups to be contained in the side chain.

The purpose of the present invention is to provide a hydrogel that bondsfirmly to the surface of various materials or to provide a variety ofapplications utilizing an adhesive hydrogel. The purpose is, by causingcatechol groups to be contained in a side chain, to provide not only ahydrogel that can be adhered more firmly than conventional adhesivehydrogels but also to make it possible to provide a hydrogel havingadjustable adhesive force and to provide a variety of applications.

The present invention relates to the following catechol-containingadhesive hydrogel, composition for preparing adhesive hydrogel,adhesive, medical adhesive, bioadhesive, ship bottom antifouling paint,water-based lubricant, and coating material for antifouling.

(1) An adhesive hydrogel having as constituent elements a water-solublemain chain monomer, a crosslinking agent, a polymerization initiator,and an adhesive monomer having a catechol group in a side chain.

(2) The adhesive hydrogel according to (1) wherein the catechol group isderived from DOPA or a derivative thereof.

(3) The adhesive hydrogel according to (1) or (2) wherein thewater-soluble main chain monomer is a vinyl group-containing monomer.

(4) An adhesive hydrogel synthesized from a water-soluble main chainmonomer, a crosslinking agent, a polymerization initiator, and anadhesive monomer having a catechol group in a side chain.

(5) The adhesive hydrogel according to (4) wherein the catechol group isderived from DOPA or a derivative thereof.

(6) The adhesive hydrogel according to (4) or (5) wherein thewater-soluble main chain monomer is a vinyl group-containing monomer.

(7) The adhesive hydrogel according to any of (1)-(6) wherein at leastone hydrogen of the catechol group is substituted by a substituentselected from a hydroxyl group, nitro group, carboxy group, and carbonylgroup.

(8) The adhesive hydrogel according to any of (1)-(7) that also includesan electrolyte.

(9) A bioadhesive that includes the adhesive hydrogel according to (8).

(10) A composition for preparing adhesive hydrogel including awater-soluble main chain monomer, a crosslinking agent, a polymerizationinitiator, and an adhesive monomer having a catechol group in a sidechain.

(11) The composition for preparing adhesive hydrogel according to (10)wherein the catechol group is derived from DOPA or a derivative thereof.

(12) The composition for preparing adhesive hydrogel according to (10)or (11) wherein the water-soluble main chain monomer is a vinylgroup-containing monomer.

(13) The composition for preparing adhesive hydrogel according to any of(10)-(12) wherein at least one hydrogen of the catechol group issubstituted by a substituent selected from a hydroxyl group, nitrogroup, carboxy group, and carbonyl group.

(14) The composition for preparing adhesive hydrogel according to any of(10)-(13) that also includes an electrolyte.

(15) An adhesive comprising a composition for preparing adhesivehydrogel according to any of (10)-(14).

(16) An adhesive containing a hydrogel wherein the adhesive according to(15) is used as a one-component adhesive where the water-soluble mainchain monomer, crosslinking agent, polymerization initiator, andadhesive monomer are included in one component or as a two-componentadhesive where the water-soluble main chain monomer, crosslinking agent,and adhesive monomer are included in a first component and thepolymerization initiator is included in a second component.

(17) A medical adhesive wherein the adhesive according to (15) or (16)is used to adhere bone, teeth, or soft tissue or to adhere bone, teeth,or soft tissue and a medical member.

(18) The medical adhesive containing a hydrogel according to (17)wherein the medical member is a sensor electrode, stimulation electrode,or implant.

(19) A ship bottom antifouling paint containing a composition forpreparing adhesive hydrogel according to any of (10)-(14).

(20) A water-based lubricant containing a composition for preparingadhesive hydrogel according to any of (10)-(14).

(21) A coating material for antifouling containing a composition forpreparing adhesive hydrogel according to any of (10)-(14).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a drawing showing the FT-IR spectrum of a DMA monomer and theFT-IR ATR spectrum of a DMA-containing hydrogel.

FIG. 2 is a drawing showing the FT-IR ATR spectrum of a double networkgel.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The adhesive monomer in the present invention is linked directly to themain chain, not through a catechol group of the side chain. Therefore,all of the catechol groups of the adhesive monomer can participate inadhesion to a substrate or the like. This makes it possible to prepare ahydrogel endowed with firm adhesiveness.

In the hydrogel of the present invention, any compound may be used asthe main chain monomer as long as the compound is a water-solublemonomer. Water-soluble vinyl group-containing monomers, polyethyleneglycol, and 2-hydroxyethyl methacrylate (HEMA) can be usedappropriately. If the monomer is a water-soluble vinyl group-containingmonomer, a water-soluble vinyl group-containing monomer of a structurerepresented by the following general formula (1) can preferably be used.

In general formula (1), R1 represents a hydrogen, C1-20 linear,branched, or cyclic alkyl group, C6-20 aryl group, or C7-20 aralkylgroup, preferably a hydrogen, C1-5 linear, branched, or cyclic alkylgroup, more preferably a hydrogen or a C3 or lower linear alkyl group,even more preferably H or CH3.

R2 represents a C1-20 linear, branched, or cyclic alkyl group, C6-20aryl group, or C7-20 aralkyl group, preferably a C1-8 linear, branched,or cyclic alkyl group, C6-8 aryl group, or C7 or 8 aralkyl group, morepreferably a C3 or lower linear alkyl group.

X represents an amide group or ester group; it need not be included, butincluding an amide group or ester group is preferred.

When X is an amide or ester and R2 is a C1-20 linear, branched, orcyclic alkyl group, examples of the monomer represented by formula (1)include methyl (meth)acrylamide, ethyl (meth)acrylamide, n-propyl(meth)acrylamide, 2-propyl (meth)acrylamide, n-butyl (meth)acrylamide,1-methylpropyl (meth)acrylamide, 2-methylpropyl (meth)acrylamide,tert-butyl (meth)acrylamide, n-pentyl (meth)acrylamide, 1-methylbutyl(meth)acrylamide, 1-ethylpropyl (meth)acrylamide, tert-pentyl(meth)acrylamide, 2-methylbutyl (meth)acrylamide, 3-methylbutyl(meth)acrylamide, 2,2-dimethylpropyl (meth)acrylamide, n-hexyl(meth)acrylamide, 1-methylpentyl (meth)acrylamide, 1-ethylbutyl(meth)acrylamide, 2-methylpentyl (meth)acrylamide, 3-methylpentyl(meth)acrylamide, 4-methylpentyl (meth)acrylamide, 2-methylpentan-3-yl(meth)acrylamide, 3,3-dimethylbutyl (meth)acrylamide, 2,2-dimethylbutyl(meth)acrylamide, 1,1-dimethylbutyl (meth)acrylamide, 1,2-dimethylbutyl(meth)acrylamide, 1,3-dimethylbutyl (meth)acrylamide, 2,3-dimethylbutyl(meth)acrylamide, 1-ethylbutyl (meth)acrylamide, 2-ethylbutyl(meth)acrylamide, heptyl (meth)acrylamide, octyl (meth)acrylamide, nonyl(meth)acrylamide, decyl (meth)acrylamide, undecyl (meth)acrylamide,dodecyl (meth)acrylamide, tridecyl (meth)acrylamide, tetradecyl(meth)acrylamide, pentadecyl (meth)acrylamide, hexadecyl(meth)acrylamide, heptadecyl (meth)acrylamide, octadecyl(meth)acrylamide, nonadecyl (meth)acrylamide, eicosyl (meth)acrylamide,cyclopropyl (meth)acrylamide, cyclobutyl (meth)acrylamide, cyclopentyl(meth)acrylamide, cyclohexyl (meth)acrylamide, and other such alkyl(meth)acrylamides; and methyl (meth)acrylate, ethyl (meth)acrylate,n-propyl (meth)acrylate, 2-propyl (meth)acrylate, n-butyl(meth)acrylate, 1-methylpropyl (meth)acrylate, 2-methylpropyl(meth)acrylate, tert-butyl (meth)acrylate, n-pentyl (meth)acrylate,1-methylbutyl (meth)acrylate, 1-ethylpropyl (meth)acrylate, tert-pentyl(meth)acrylate, 2-methylbutyl (meth)acrylate, 3-methylbutyl(meth)acrylate, 2,2-dimethylpropyl (meth)acrylate, n-hexyl(meth)acrylate, 1-methylpentyl (meth)acrylate, 1-ethylbutyl(meth)acrylate, 2-methylpentyl (meth)acrylate, 3-methylpentyl(meth)acrylate, 4-methylpentyl (meth)acrylate, 2-methylpentan-3-yl(meth)acrylate, 3,3-dimethylbutyl (meth)acrylate, 2,2-dimethylbutyl(meth)acrylate, 1,1-dimethylbutyl (meth)acrylate, 1,2-dimethylbutyl(meth)acrylate, 1,3-dimethylbutyl (meth)acrylate, 2,3-dimethylbutyl(meth)acrylate, 1-ethylbutyl (meth)acrylate, 2-ethylbutyl(meth)acrylate, and other such alkyl (meth)acrylates.

When X is an amide or ester and R2 is a C6-20 aryl group, examplesinclude phenyl (meth)acrylamide, indenyl (meth)acrylamide, pentalenyl(meth)acrylamide, naphthyl (meth)acrylamide, azulenyl (meth)acrylamide,fluorenyl (meth)acrylamide, and other such aryl (meth)acrylamides.

When X is an amide or ester and R2 is a C7-20 aralkyl group, examplesinclude benzyl (meth)acrylamide and other such aralkyl (meth)acrylamidesand benzyl (meth)acrylate and other such aralkyl (meth)acrylates.

On the other hand, examples of the monomer when X is not included informula (1) and R2 is a C1-20 linear, branched, or cyclic alkyl groupinclude propylene, 2-methyl-1-propylene, 1-butene, 2-methyl-1-butene,3-methyl-1-butene, 3,3-dimethyl-1-butene, 3-methyl-2-ethyl-1-butene,2,3-dimethyl-1-butene, 2-tert-butyl-3,3-dimethyl-1-butene,cyclopropylene, cyclobutene, cyclopentene, or cyclohexene.

Examples of the monomer when X is not included in formula (1) and R2 isa C6-20 aryl group include vinylbenzene (styrene) and other such vinylaryls.

Examples of the monomer when X is not included in formula (1) and R2 isa C7-20 aralkyl group include 3-phenyl-1-propylene,2-phenyl-1-propylene, 4-phenyl-1-butene, 3-phenyl-1-butene,2-phenyl-1-butene, 5-phenyl-1-pentene, 4-phenyl-1-pentene,3-phenyl-1-pentene, 2-phenyl-1-pentene, 6-phenyl-1-hexene,5-phenyl-1-hexene, 4-phenyl-1-hexene, 3-phenyl-1-hexene,2-phenyl-1-hexene, 7-phenyl-heptene, 6-phenyl-heptene,5-phenyl-1-heptene, 4-phenyl-1-heptene, 3-phenyl-1-heptene,2-phenyl-1-heptene, 8-phenyl-1-octene, 7-phenyl-1-octene,6-phenyl-1-octene, 5-phenyl-1-octene, 4-phenyl-1-octene, 3phenyl-1-octene, 2-phenyl-1-octene, 9-phenyl-1-nonene, 8phenyl-1-nonene, 7-phenyl-1-nonene, 6-phenyl-1-nonene, 5phenyl-1-nonene, 4-phenyl-1-nonene, 3-phenyl-1-nonene, 2phenyl-1-nonene, 10-phenyl-1-decene, 9-phenyl-1-decene,8-phenyl-1-decene, 7-phenyl-1-decene, 6-phenyl-1-decene, 5phenyl-1-decene, 4-phenyl-1-decene, 3-phenyl-1-decene, 2phenyl-1-decene, 11-phenyl-1-undecene, 10-phenyl-1-undecene,9-phenyl-1-undecene, 8-phenyl-1-undecene, 7-phenyl-1-undecene,6-phenyl-1-undecene, 5-phenyl-1-undecene, 4-phenyl-1-undecene,3-phenyl-1-undecene, 2-phenyl-1-undecene, 12-phenyl-1-dodecene,11-phenyl-1-dodecene, 10-phenyl-1-dodecene, 9-phenyl-1-dodecene,8-phenyl-1-dodecene, 7-phenyl-1-dodecene, 6-phenyl-1-dodecene,5-phenyl-1-dodecene, 4-phenyl-1-dodecene, 3-phenyl-1-dodecene,2-phenyl-1-dodecene, 13-phenyl-1-tridecene, 12-phenyl-1-tridecene,11-phenyl-1-tridecene, 10-phenyl-1-tridecene, 9-phenyl-1-tridecene,8-phenyl-1-tridecene, 7-phenyl-1-tridecene, 6-phenyl-1-tridecene,5-phenyl-1-tridecene, 4-phenyl-1-tridecene, 3-phenyl-1-tridecene,2-phenyl-1-tridecene, 14-phenyl-1-tetradecene, 13-phenyl-1-tetradecene,12-phenyl-1-tetradecene, 11-phenyl-1-tetradecene,10-phenyl-1-tetradecene, 9-phenyl-1-tetradecene, 8-phenyl-1-tetradecene,7-phenyl-1-tetradecene, 6-phenyl-1-tetradecene, 5-phenyl-1-tetradecene,4-phenyl-1-tetradecene, 3-phenyl-1-tetradecene, 2-phenyl-1-tetradecene,and the like. In addition, these monomers may be used in combinationwith other organic monomers.

Crosslinking agents capable of introducing a three-dimensionalcrosslinked structure by polymerizable double bonds are broadly includedas the crosslinking agent. Specific examples include N,N′-methylenebis(meth)acrylamide, N,N′-(1,2-dihydroxyethylene)-bis(meth)acrylamide,diethylene glycol di(meth)acrylate, (poly)ethylene glycoldi(meth)acrylate, triethylene glycol di(meth)acrylate, propylene glycoldi(meth)acrylate, trimethylolpropane di(meth)acrylate,trimethylolpropane tri(meth)acrylate, pentaerythritol di(meth)acrylate,pentaerythritol tri(meth)acrylate, pentaerythritol tetra(meth)acrylate,(poly) propylene glycol di(meth)acrylate, glycerin tri(meth)acrylate,glycerin acrylate methacrylate, ethylene oxide-modifiedtrimethylolpropane tri(meth)acrylate, pentaerythritoltetra(meth)acrylate, dipentaerythritol hexa(meth)acrylate, and othersuch divinyl compounds; triallyl cyanurate, triallyl isocyanurate,triallyl phosphate, triallylamine, poly(meth)allyloxy alkane,(poly)ethylene glycol diglycidyl ether, glycerol diglycidyl ether,ethylene glycol, polyethylene glycol, propylene glycol, glycerin,pentaerythritol, ethylenediamine, polyethyleneimine, glycidyl(meth)acrylate, triallyl isocyanurate, trimethylolpropane di(meth)allylether, tetraallyloxyethane, glycerol propoxy triacrylate, and the like.These crosslinking agents can be used individually or in combinations oftwo or more types.

The adhesive polymer having a catechol group in the present inventioncan be produced by the method described in Non-patent Document 3. Here,an adhesive monomer containing a catechol group was prepared frommethacrylic anhydride and dopamine hydrochloride, but adhesive monomerscan be prepared by using water-soluble vinyl group-containing monomersthe same as the main chain monomer in place of methacrylic anhydride.For example, compounds represented by the following general formula (2)can be used as the adhesive monomer.

In general formula (2), R3 represents a hydrogen or C1-20 alkyl group;it may be linear, branched, or cyclic, and a hydrogen or C1-5 alkylgroup is preferred. More preferred is a hydrogen or a C3 or lower linearalkyl group, even more preferred is H or CH3. Y represents an amide orester, but need not be included. p represents 0 or an integer of 1-10,preferably 0 or an integer of 1-5, more preferably 0 or an integer of1-3, even more preferably 2.

When Y is an amide, examples of such monomers includeN-[2-(3,4-dihydroxyphenyl)methyl] (meth)acrylamide,N-[2-(3,4-dihydroxyphenyl)ethyl] (meth)acrylamide (sometimes referred tohereinafter as dopamine (meth)acrylamide, and sometimes abbreviatedsimply as DMA), N-[2-(3,4-dihydroxyphenyl)propyl] (meth)acrylamide,N-[2-(3,4-dihydroxyphenyl)butyl] (meth)acrylamide,N-[2-(3,4-dihydroxyphenyl)pentyl] (meth)acrylamide,N-[2-(3,4-dihydroxyphenyl)hexyl] (meth)acrylamide,N-[2-(3,4-dihydroxyphenyl)heptyl] (meth)acrylamide,N-[2-(3,4-dihydroxyphenyl)octyl] (meth)acrylamide,N-[2-(3,4-dihydroxyphenyl)nonyl] (meth)acrylamide, andN-[2-(3,4-dihydroxyphenyl)decyl] (meth)acrylamide.

When Y is an ester, examples include N-[2-(3,4-dihydroxyphenyl)methyl](meth)acrylate, N-[2-(3,4-dihydroxyphenyl)ethyl] (meth)acrylate(sometimes referred to as dopamine (meth)acrylate),N-[2-(3,4-dihydroxyphenyl)propyl] (meth)acrylate,N-[2-(3,4-dihydroxyphenyl)butyl] (meth)acrylate,N-[2-(3,4-dihydroxyphenyl)pentyl] (meth)acrylate,N-[2-(3,4-dihydroxyphenyl)hexyl] (meth)acrylate,N-[2-(3,4-dihydroxyphenyl)heptyl] (meth)acrylate,N-[2-(3,4-dihydroxyphenyl)octyl] (meth)acrylate,N-[2-(3,4-dihydroxyphenyl)nonyl] (meth)acrylate, andN-[2-(3,4-dihydroxyphenyl)decyl] (meth)acrylate.

When Y is not included, examples include 3,4-dihydroxystyrene,3-(3,4-dihydroxyphenyl)-1-propene, 4-(3,4-dihydroxyphenyl)-1-butene,5-(3,4-dihydroxyphenyl)-1-pentene, 6-(3,4-dihydroxyphenyl)-1-hexene,7-(3,4-dihydroxyphenyl)-1-heptene, 8-(3,4-dihydroxyphenyl)-1-octene,9-(3,4-dihydroxyphenyl)-1-nonene, 10-(3,4-dihydroxyphenyl)-1-decene,3-(3,4-dihydroxyphenyl)-2-methyl-1-propene,4-(3,4-dihydroxyphenyl)-2-methyl-1-butene,5-(3,4-dihydroxyphenyl)-2-methyl-1-pentene,6-(3,4-dihydroxyphenyl)-2-methyl-1-hexene,7-(3,4-dihydroxyphenyl)-2-methyl-1-heptene,8-(3,4-dihydroxyphenyl)-2-methyl-1-octene,9-(3,4-dihydroxyphenyl)-2-methyl-1-nonene, and10-(3,4-dihydroxyphenyl)-2-methyl-1-decene.

The adhesiveness of the hydrogel is proportionate to the number ofcatechol groups contained in the hydrogel. Therefore, when firmadhesiveness is required, one may increase the amount of adhesivemonomer including catechol groups in the side chain. In other words, thedesired adhesive strength can be obtained by adjusting the amount ofadhesive monomer.

One or more substituents may be introduced at R4-R6 in the followinggeneral formula (3) as an adhesive monomer for imparting adhesiveness inthe present invention. In other words, the side chain may include agroup in which a hydrogen of the catechol group has been substituted bya substituent. A hydroxyl group, nitro group, carboxy group, carbonylgroup, or the like can be contained as a substituent. When substituentsare introduced, the same groups may be introduced or different groupsmay be introduced. Introducing substituents at R4-R6 can weaken theadhesiveness in comparison to when the side chain is made from catecholgroups. When firm adhesiveness is not required, the strength ofadhesiveness can be adjusted not only by adjusting the amount ofadhesive monomer but also by using an adhesive monomer in whichsubstituents such as a hydroxyl group, nitro group, carboxy group, orcarbonyl group have been introduced.

One derived from DOPA or a derivative thereof is preferred as theadhesive monomer having a catechol group used in the present inventionfor performance and ease of production. One derived from DOPA is morepreferred in terms of ease of availability. Here, one derived from DOPAor a derivative thereof means one represented by p=2 among thoserepresented by the above general formula (2) or (3), and one derivedfrom DOPA is preferred for the ease of production. Specifically, thismeans one that can be synthesized form DOPA(3,4-dihydroxyphenylalanine), more preferably dopamine (meth)acrylamideor dopamine (meth)acrylate. Dopamine (meth)acrylamide is more preferredfor the ease of production.

The adhesive monomer having a catechol group may be added in aproportion of usually 1% or more, preferably 3% or more, more preferably5% or more, even more preferably 8% or more, and usually 50% or less,preferably 30% or less, more preferably 20% or less, and even morepreferably 15% or less, relative to the total number of mol of mainchain monomer and adhesive monomer.

Any such as a photopolymerization initiator, thermal polymerizationinitiator, or the like may be used as the polymerization initiator, buta photopolymerization initiator is preferably used. Thephotopolymerization initiator is not particularly restricted as long asit is cleaved by ultraviolet rays or visible light rays to generateradicals. Examples include 2,2′-azobis-N-(2-hydroxyethyl)propionamide,2,2′-azobis(1-imino-1-pyrrolidino-2-methylpropane)dihydrochloride, andother such azo polymerization initiators; α-hydroxyketone,α-aminoketone, benzyl methyl ketal, bisacylphosphine oxide, metallocene,and the like; more specifically,1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-propan-1-one (productname: IRGACURE (registered trade mark) 2959, manufactured by BASFJapan), 2-hydroxy-2-methyl-1-phenyl-propan-1-one (product name: Darocur(registered trade mark) 1173, manufactured by BASF Japan),1-hydroxy-cyclohexyl-phenyl-ketone (product name: IRGACURE (registeredtrade mark) 184, manufactured by BASF Japan),2-methyl-1-[(methylthio)phenyl]-2-morpholinopropan-1-one (product name:IRGACURE (registered trade mark) 907, manufactured by BASF Japan),2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-butan-1-one (productname: IRGACURE (registered trade mark) 369, manufactured by BASF Japan),and the like. These photopolymerization initiators may be usedindividually or in combinations of two or more types.

The adhesive hydrogel of the present invention can be obtained bypolymerizing the above constituent elements. Specifically, a compositionincluding the water-soluble main chain monomer, crosslinking agent, andadhesive monomer containing a catechol group in a side chain(hereinafter, composition for hydrogel production) can be prepared andpolymerized.

The polymerization method is not particularly restricted as long as astructure having the adhesive monomer including a catechol group as aside chain is obtained relative to the water-soluble main chain monomer.

The method of polymerization is not particularly restricted, andcommonly used polymerization methods are used. However, solutionpolymerization is preferred. The adhesive hydrogel of the presentinvention is usually polymerized by dissolving the constituent elementsin a solution including water. Other polar solvents can be used incombination as long as they do not inhibit the performance of theadhesive hydrogel or the polymerization reaction. The use of other polarsolvents can improve the solubility of the water-soluble main chainmonomer and adhesive monomer. The concentration of the reaction solutionwhen these monomer components have been dissolved is not particularlyrestricted, but 0.1 M or higher is preferred.

The polar solvent is not particularly restricted. Specifically,dimethylsulfoxide (DMSO), methanol, N-methylpyrrolidone (NMP), ionicliquids, and the like can be used; DMSO is preferred for copolymerizingan adequate amount of adhesive monomer.

The hydrogel obtained by the polymerization reaction has strongadhesiveness. Although the structure is not particularly restricted, thehydrogel has a structure in which the water-soluble monomer has beenpolymerized as the main chain and the adhesive monomer having a catecholgroup has been polymerized as a side chain. The mode of polymerizationis not particularly restricted, but the hydrogel is usually a randomcopolymer. Among structures having an adhesive monomer, specificallywhen the adhesive monomer is a vinyl group-containing monomer, the vinylgroups serve as crosslinking points and form bonds with the crosslinkingagent. On the other hand, the hydrogel has a structure in which catecholgroups are present in the polymer in a free state. The catechol groupsfunction as adhesible points and actualize the function of an adhesivehydrogel.

The pH of the hydrogel of the present invention is not particularlyrestricted, but is usually 10 or lower, preferably 9 or lower. This isbecause adequate adhesiveness can be obtained by a pH within this rangesince hydrogen bonding capacity is not inhibited.

The hydrogel of the present invention can be used as a one-componentadhesive or a two-component adhesive. When used as a one-componentadhesive, the water-soluble main chain monomer, crosslinking agent,polymerization initiator, and adhesive monomer (composition for hydrogelproduction) may be contained in one component. When used as atwo-component adhesive, the water-soluble main chain monomer,crosslinking agent, and adhesive monomer may be included in a firstcomponent and the polymerization initiator in a second component.

Thickening agents, surfactants, antioxidants, light resistancestabilizers, defoaming agents, plasticizers, pigments, and other suchcoloring agents may also be added as needed to improve the processsuitability and adhesiveness of these adhesives. Other aqueousdispersions, for example, vinyl acetate-based, ethylene-vinylacetate-based, acrylic, acrylic-styrene-based, and other such emulsions;styrene-butadiene-based, acrylonitrile-butadiene-based,acrylic-butadiene-based, and other such latexes; polyethylene-based,polyolefin-based, and other such ionomers; polyurethane, polyester,polyamide, epoxy-based resins, and the like may also be admixed withinthe range that does not harm the effects of the present invention.

The adhesive of the present invention can firmly adhere the hydrogel tothe surface of various materials. For example, it has adhesiveness toinorganic materials such as hydroxyapatite, titanium oxide, zinc oxide,iron oxide, and glass, metals such as iron, gold, silver, and titanium,and resins such as polytetrafluoroethylene (PTFE) and polyimide.Hydrogels of different compositions can also be adhered to a substrateby utilizing the adhesiveness to the surfaces of these materials.Applications such as the following are therefore possible.

An adhesive made from the hydrogel composition of the present inventioncan be used as a medical adhesive to adhere bone, teeth, or soft tissueor to adhere bone, teeth, or soft tissue and a medical device. Theadhesive can be used as a hard tissue adhesive to adhere hard tissuessuch as bones and teeth. For example, the adhesive can be used bone andartificial bone in a surgical procedure, and repair broken teeth and inadhesive bridges in the dental field. It can also be used for woundadhesion and surgical anastomoses as an adhesive of the skin,gastrointestinal tract, blood vessels, trachea, and other such softtissues.

Furthermore, the adhesive can be used to adhere these tissues and asensor electrode, stimulation electrode, implant, or other such medicalmember. Since the hydrogel endowed with adhesiveness of the presentinvention is endowed with firm adhesiveness, it is suitable for use as awearable device for attaching a sensor electrode or stimulationelectrode to the body for health management, diagnosis, or treatment. Itcan also be used as a suitable adhesive for immobilizing dental and boneimplants. Pigments, drugs, and other such optional additives may beadded as needed when used as a medical adhesive.

The adhesive hydrogel of the present invention can also be used as acoating material for antifouling to prevent proteins and cells fromadhering to implantable medical devices such as catheters, stents, andcardiac pacemakers. For example, urinary tract infections triggered bymicroorganisms forming colonies in catheters are a problem as a frequentnosocomial infection. The adhesion of microorganisms to these medicaldevices can be prevented by coating them with hydrogel. Known pigments,antimicrobials, and other such optional additives may be added as neededwhen the adhesive hydrogel of the present invention is used as a coatingmaterial for antifouling.

Furthermore, the adhesive hydrogel of the present invention can also beused as a peelable adhesive by using one with weakened adhesiveness bydecreasing the content of catechol groups or by substituents such asnitro groups or hydroxyl groups. The adhesive becomes peelable byweakening the adhesiveness, and it can be used suitably as a bioadhesivesince it can be used repeatedly. It can also be used as an electrodeused by affixing an EMS (electrical muscle stimulation) or other suchhealth device electrode, ECG electrode, low frequency treatment deviceelectrode, or the like to the skin by adding an electrolyte to thehydrogel. The following electrolytes may be contained in the aqueoussolution when preparing the hydrogel when the bioadhesive is used as anelectrode.

Any compound may be used as an electrolyte as long as it generatescations and anions in aqueous solution. Those that generate a sodiumion, potassium ion, magnesium ion, calcium ion, chloride ion, phosphateion, and other such electrolyte ions can preferably be used.Specifically, a sodium halide such as sodium chloride, potassium halide,magnesium halide, calcium halide, or other such alkali metal halide,alkaline earth metal halide, or the like may be contained in the aqueoussolution. Salts of an inorganic acid such as hypochlorous acid, sulfuricacid, and phosphoric acid and various metals, ammonium salts of theseinorganic acids, various metal salts and ammonium salts ofmonocarboxylic acids such as acetic acid, benzoic acid, and lactic acid,salts of one or more metals or ammonia and polycarboxylic acids such asphthalic acid, succinic acid, adipic acid, citric acid, and tartaricacid, and the like can also be used. These electrolytes may be usedindividually, or configured so that two or more types are contained inthe aqueous solution during production of the hydrogel. They may also beused by immersing the hydrogel in an aqueous solution containing theelectrolyte after hydrogel production to substitute the water in thehydrogel by electrolyte solution.

The hydrogel of the present invention can also be made to include anelectrolyte and used to affix an electrode to a building or the like.For example, the hydrogel of the present invention can be used whenadhering an electrode to a bridge of the like. Since an electrolyte isincluded, an electric current can be applied by pasting an electrode toa building such as a bridge. The adhesiveness is good and adhesion issimple since the hydrogel adheres well even if rust forms. The sameelectrolytes as the above may be added as the electrolyte when pastingan electrode to a building.

The adhesive hydrogel of the present invention can also be used as aship bottom antifouling paint. The common method for preventingbiofouling is to fix an antifouling polymer to the surface. Since thehydrogel of the present invention can adhere firmly to metals such asiron, the ship's bottom can be coated with hydrogel. Coating the bottomof the ship by hydrogel can prevent sea creatures such as barnacles fromadhering to the bottom of the ship. Organic antifouling components,plasticizers, inorganic dehydrating agents (stabilizers), antisaggingagents, antisettling agents, coloring pigments, rust inhibitors, and thelike may be added as needed when the adhesive hydrogel of the presentinvention is used as a ship bottom antifouling paint.

The composition for preparing adhesive hydrogel of the present inventioncan also be used suitably as a water-based lubricant. If a hydrogel withhigh biocompatibility is used, it can be used as a lubricant between animplant and a bone or even as a lubricant for machine parts that use awater-based lubricant such as in cutting. A water-based lubricant of thepresent invention may contain components known as constituent componentsof lubricant compositions, such as rust inhibitors, binders, defoamingagents, foaming agents, emulsifiers, preservatives, and the like, asneeded.

The adhesive hydrogel of the present invention can be used withoutmodification as a coating material for antifouling, ship bottomantifouling paint, and water-based lubricant by coating a base material.A base material can also be coated by the adhesive hydrogel and anon-adhesive hydrogel coated on top of that, for use as a coatingmaterial for antifouling and the like.

Example 1

<<Production of Adhesive Hydrogel>>

A prepolymer aqueous solution was adjusted using 950 mM of acrylamide aswater-soluble main chain monomer, 13.0 mM of N,N-methylenebisacrylamideas crosslinking agent, 65.6 mM of 2-hydroxy-2-methylpropiophenone aspolymerization initiator, and 50 mM of dopamine methacrylamide (DMA) asadhesive monomer. An aqueous solution obtained by adding DMSO to make3.3 mL to 6.7 mL of PBS (2.68 mM KCl, 136.9 mM NaCl, 8.05 mM Na₂HPO₄,1.47 mM KH₂PO₄) was used as the solvent. The adjusted prepolymer aqueoussolution was nitrogen bubbled for two minutes to remove oxygen whichinhibits polymerization. Adding DMSO to the aqueous solution permitspolymerization even if the polarity of the catechol groups to whichpolymerizable groups have been imparted decreases.

The prepolymer aqueous solution was cast on a UV-permeable acrylicplate, irradiated for six hours with 1 mW/cm² of light having awavelength of 300 nm in a nitrogen atmosphere, and a polymerizedhydrogel was synthesized. The composition of the hydrogel obtained wasconfirmed by Fourier transform infrared attenuated total reflectance(FT-IR ATR) using an FT/IR6100 (manufactured by Jasco).

FIG. 1 shows the results of FT-IR ATR analysis of the DMA monomer andthe hydrogel including DMA. A stretching vibration from the amide of theacrylamide (shown by the dotted arrow in the drawing) and a peak fromthe catechol group (shown by the solid arrow in the drawing) wereobtained. DMA was introduced as a side chain in the gel mixed with DMA,and DMA was confirmed to be present on the gel surface.

Example 2

<<Study of Hydrogel Adhesiveness>>

A prepolymer aqueous solution was adjusted by varying the DMAconcentration from 0 to 200 mM so that the sum with acrylamide would be1000 mM. Table 1 shows the composition of the aqueous solution. Aquantity of 30 μL of the prepared solution was placed between two slideglasses so that the adhered surface would be 20 mm×26 mm, irradiated forsix hours by 1 mW/cm² of light having a wavelength of 300 nm in anitrogen atmosphere, and polymerized.

TABLE 1 Sample 1 2 3 4 DMA   0 mM  50 mM 100 mM 200 mM Acrylamide 1000mM 950 mM 900 mM 800 mM N,N′-methylenebisacrylamide 13.0 mM2-Hydroxy-2-methylpropiophenone 65.6 mM Solvent PBS (6.7 mL) + DMSO (3.3mL)

A lap shear test was conducted using the samples prepared. The hydrogelobtained was set in a tensile tester (manufactured by Imada Co., Ltd.,DPU), pulled at a rate of 10 mm/min, and the peeling stress of thehydrogel was measured by a lap shear test. Each lap shear test wasconducted three times, and the average value was calculated as thepeeling stress.

Lap shear tests were conducted on a DMA-free hydrogel sample 1 andhydrogel samples 2, 3, and 4 including the concentrations of DMA shownin Table 1. While the peeling stress of sample 1 was 0.93 kPa, that ofsample 2 (DMA concentration 50 mM) was 14.9 kPa, that of sample 3 (DMAconcentration 100 mM) was 31.8 kPa, and that of sample 4 (DMAconcentration 200 mM) was 13.9 kPa.

Sample 3 was able to obtain strength at least 30 times greater than theDMA-free sample 1. Adhesive force greater than sample 3 was not obtainedeven at the maximum DMA content of 200 mM. This is thought to be becausethe pH decreases rapidly (pH 5 and below) as the DMA content increasesand inhibits the hydrogen bonding capacity. A hydrogel with higheradhesiveness can also be prepared by adjusting the pH, but the contentof adhesive monomer is preferably 50% or less relative to the totalnumber of moles of main chain monomer and adhesive monomer inconsideration of the water solubility of the catechol groups.

Example 3

<<Study of Hydrogel Adhesiveness to Different Base Materials>>

Acrylamide (60 mg/mL), DMA (20 mg/mL), N,N-methylenebisacrylamide (20mg/mL), and IRGACURE 2959 (10 μg/mL) were dissolved in 6.7 mL of PBSbuffer (pH 7) and 3.3 mL of DMSO, cast on glass and metal substrates,the surface of which had been cleaned by oxygen plasma (100 W, for oneminute), collagen gel, soft contact lens, and Teflon (registered trademark) substrates, and photopolymerized under the same conditions as inExample 1.

When it was checked whether the hydrogel could be pulled off withtweezers, the hydrogel adhered stably without peeling in all casesexcept the Teflon substrate. This result confirmed that DMA-containinghydrogel can be peeled from a Teflon substrate and adheres firmly toother substrates. Although the results are not shown here, the hydrogelcould also adhere to base materials such as silver, titanium, titaniumoxide, iron oxide, and zinc oxide endowed with similar surfacecharacteristics.

Example 4

<<DMA-Containing Hydrogel Formation on Hydrogel Surface>>

Formation of a DMA-containing hydrogel on the surface of a doublenetwork (sometimes abbreviated hereinafter as DN) gel was attempted. DNgel was synthesized by the following method. Sodium2-acrylamide-2-methyl-1-propanesulfonate, N,N′-methylenebisacrylamide,and 2-oxoglutaric acid were prepared in respective concentrations of 1M, 40 mM, and 1 mM. The solution was placed between glass plates, and aninitial gel was synthesized by polymerizing for six hours in a nitrogenatmosphere while irradiating with UV light at an intensity of 1 mW/cm².Thereafter, dimethylacrylamide, N,N′-methylenebisacrylamide, and2-oxoglutaric acid were each prepared in concentrations of 3 M, 3 mM,and 3 mM, the gel was soaked for two nights and polymerized in the sameway to synthesize a DN gel.

A quantity of 50 III, of the prepolymer solution of DMA shown in sample4 of Example 2 was cast on a Teflon substrate, and 15 mm² of the 0.5 mmthick DN gel synthesized was placed on it. Photopolymerization wasconducted thereafter for 20 minutes under the same conditions as inExample 2, and the sample was gelled. The hydrogel obtained was peeledfrom the Teflon substrate, and the composition of the air side andTeflon substrate side of the gel was measured by FT-IR-ATR.

FIG. 2 shows the FT-IR-ATR spectra of the side facing the Teflon (Teflonside), which was the substrate, and the side facing the air (air side).While only a strong peak from the amide of acrylamide was observed onthe air side, an absorption peak (shown by an arrow in the drawing) fromDMA was observed on the Teflon side. As shown in FIG. 2, aDMA-containing hydrogel can be formed on a specific surface of ahydrogel. In other words, it is possible to form an adhesiveDMA-containing hydrogel on the substrate side and to position anon-adhesive hydrogel on the surface. This permits applications such ascovering the surface of implants and artificial joints that requirelubricity by hydrogel and preventing barnacles and other such organismsfrom adhering by coating ship bottoms with hydrogel.

INDUSTRIAL APPLICABILITY

The adhesive hydrogel of the present invention is endowed with firmadhesiveness and can be utilized in adhesives and hydrogel coatingbecause it can bond to various base materials. Specifically, it can beutilized as a medical adhesive, coating material for antifouling, shipbottom antifouling paint, and water-based lubricant. When the adhesivehydrogel of the present invention is used as a coating material forantifouling, ship bottom antifouling paint, or water-based lubricant,the base material may be used as is coated by adhesive hydrogel or withthe base material coated by adhesive hydrogel and also coated byhydrogel.

What is claimed is:
 1. A composition for preparing adhesive hydrogelincluding a water-soluble main chain monomer, a crosslinking agent, apolymerization initiator, an adhesive monomer having a catechol group ina side chain, and water, provided that any inorganic nano-silicate innot included.
 2. The composition for preparing adhesive hydrogelaccording to claim 1, wherein the adhesive monomer is added in aproportion of 8% or more to the total number of mol of the main chainmonomer and the adhesive monomer.
 3. The composition for preparingadhesive hydrogel according to claim 1, wherein the catechol group isderived from DOPA or a derivative thereof.
 4. The composition forpreparing adhesive hydrogel according to claim 1, wherein thewater-soluble main chain monomer is a vinyl group-containing monomer. 5.The composition for preparing adhesive hydrogel according to claim 1,further comprising an electrolyte and/or a polar solvent.
 6. Thecomposition for preparing adhesive hydrogel according to claim 1,wherein the crosslinking agent is a crosslinking agent capable ofintroducing a three-dimensional crosslinked structure by polymerizabledouble bonds.
 7. A method of applying an amount of the composition ofclaim 1 onto a ship bottom effective to antifoul paint.
 8. A method ofcoating a base material with an amount of the composition of claim 1effective to lubricate the top of the base material.
 9. A method ofapplying an amount of the composition of claim 1 onto a base materialeffective to antifoul the base material.
 10. A method for synthesizingan adhesive hydrogel including (i) a step of preparing a prepolymeraqueous solution containing a composition of claim 1, and (ii) apolymerization initiation step for conducting a polymerizationinitiation reaction in the prepolymer aqueous solution.
 11. Thecomposition for preparing adhesive hydrogel according to claim 1,substantially composed of a water-soluble main chain monomer, acrosslinking agent, a polymerization initiator, an adhesive monomerhaving a catechol group in a side chain, agents which are used to makebuffer action in the adhesive hydrogel and water, and wherein theadhesive monomer is added in a proportion of 5% or more to the totalnumber of mol of the main chain monomer and the adhesive monomer. 12.The composition for preparing adhesive hydrogel according to claim 11,wherein the adhesive monomer is added in a proportion of 8% or more tothe total number of mol of the main chain monomer and the adhesivemonomer.
 13. The composition for preparing adhesive hydrogel accordingto claim 11, wherein the catechol group is derived from DOPA or aderivative thereof.
 14. The composition for preparing adhesive hydrogelaccording to claim 11, wherein the water-soluble main chain monomer is avinyl group-containing monomer.
 15. The composition for preparingadhesive hydrogel according to claim 11, further comprising anelectrolyte and/or a polar solvent.
 16. The composition for preparingadhesive hydrogel according to claim 11, wherein the crosslinking agentis a crosslinking agent capable of introducing a three-dimensionalcrosslinked structure by polymerizable double bonds.
 17. A method ofapplying an amount of the composition of claim 11 onto a ship bottomeffective to antifoul paint.
 18. A method of coating a base materialwith an amount of the composition of claim 11 effective to lubricate thetop of the base material.
 19. A method of applying an amount of thecomposition of claim 11 onto a base material effective to antifoul thebase material.
 20. A method for synthesizing an adhesive hydrogelincluding (i) a step of preparing a prepolymer aqueous solutioncontaining a composition of claim 11, and (ii) a polymerizationinitiation step for conducting a polymerization initiation reaction inthe prepolymer aqueous solution.
 21. A method of (i) adhering bone,teeth, or soft tissues, or (ii) of adhering bone, teeth, or soft tissueand a medical member, with an adhesive in a medical field, the adhesivecomprising a composition for preparing adhesive hydrogel including: awater-soluble main chain monomer, a crosslinking agent, a polymerizationinitiator, an adhesive monomer having a catechol group in a side chain,and water, wherein the adhesive monomer is added in a proportion of 5%or more to the total number of mol of the main chain monomer and theadhesive monomer, and wherein all of the catechol groups of the adhesivemonomer can participate in adhesion to a substrate and the hydrogel hasa structure in which the catechol groups are present in the polymer in afree state.
 22. The method of adhering according to claim 21, whereinthe medical member is a sensor electrode, a stimulation electrode, or animplant.